Development of a Pediatric Relative Bioavailability/Bioequivalence Database and Identification of Putative Risk Factors Associated With Evaluation of Pediatric Oral Products

Pawar, Gopal; Wu, Fang; Zhao, Liang; Fang, Lanyan; Burckart, Gilbert J.; Feng, Kairui; Mousa, Youssef M.; Naumann, Franci; Batchelor, Hannah

doi:10.1208/s12248-021-00592-y

Cited by 6 publications

(9 citation statements)

References 103 publications

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“…The novel output from this study will improve the physiological understanding of the paediatric colon, aid biopredictive in silico simulations and establishing novel, more accurate in vitro assays and thus support paediatric drug development that targets the colon, resulting in more age-appropriate medicines for the paediatric population [ 71 , 72 ].…”

Section: Discussionmentioning

confidence: 99%

Quantification of Fluid Volume and Distribution in the Paediatric Colon via Magnetic Resonance Imaging

et al. 2021

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Previous studies have used magnetic resonance imaging (MRI) to quantify the fluid in the stomach and small intestine of children, and the stomach, small intestine and colon of adults. This is the first study to quantify fluid volumes and distribution using MRI in the paediatric colon. MRI datasets from 28 fasted (aged 0–15 years) and 18 fluid-fed (aged 10–16 years) paediatric participants were acquired during routine clinical care. A series of 2D- and 3D-based software protocols were used to measure colonic fluid volume and localisation. The paediatric colon contained a mean volume of 22.5 mL ± 41.3 mL fluid, (range 0–167.5 mL, median volume 0.80 mL) in 15.5 ± 17.5 discreet fluid pockets (median 12). The proportion of the fluid pockets larger than 1 mL was 9.6%, which contributed to 94.5% of the total fluid volume observed. No correlation was detected between all-ages and colonic fluid volume, nor was a difference in colonic fluid volumes observed based on sex, fed state or age group based on ICH-classifications. This study quantified fluid volumes within the paediatric colon, and these data will aid and accelerate the development of biorelevant tools to progress paediatric drug development for colon-targeting formulations.

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Section: Discussionmentioning

confidence: 99%

Quantification of Fluid Volume and Distribution in the Paediatric Colon via Magnetic Resonance Imaging

et al. 2021

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“…24,25 Typically, such studies are conducted in adults. 26 For fexofenadine HCl, similar exposures have been demonstrated with tablets, ODTs, and suspensions in children and adults. 30,32,39,49 Thus, while the present study was conducted in healthy adult volunteers, and not in pediatric patients, these previous studies demonstrating similar exposures to fexofenadine HCl in these patient populations, with appropriate dosing.…”

Section: Discussionmentioning

confidence: 68%

“…25 Moreover, bioavailability and bioequivalence studies are generally conducted in adult populations. 26 The pharmacokinetics of fexofenadine HCl are well characterized in healthy adults [27][28][29] and in children with SAR 30,31 and CIU. 32 Fexofenadine is rapidly absorbed (T max 1.4-1.5 hours) and has an absolute bioavailability of 35% after oral administration.…”

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confidence: 99%

Bioequivalence of 2 Pediatric Formulations of Fexofenadine Hydrochloride Oral Suspension

Rauch,

Lucio,

De Fer

et al. 2023

Clinical Pharm in Drug Dev

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Fexofenadine hydrochloride (HCl) is a second‐generation, nonsedating, histamine H1‐receptor antagonist used to manage seasonal allergic rhinitis and chronic idiopathic urticaria. A new oral pediatric suspension of fexofenadine HCl has been developed, with the preservative potassium sorbate replacing parabens. The objective of this phase 1 single‐center, open‐label, randomized, 2‐treatment, full‐replicated, 4‐period, 2‐sequence crossover study in healthy adult volunteers was to assess the bioequivalence of 30 mg of the new oral suspension of fexofenadine HCl (test) versus 30 mg of the marketed pediatric oral suspension of fexofenadine HCl (reference). The replicate design was based on the high intra‐individual variability of fexofenadine (>30% on Cmax). The study comprised 68 randomized and treated volunteers. Plasma concentrations of fexofenadine were similar following the administration of a single dose of each formulation. Cmax, AUClast, AUC, median tmax, and mean t1/2z were similar between administrations of the same fexofenadine formulation and between formulations. A high intra‐individual variability was confirmed with both formulations. Bioequivalence of the test and reference fexofenadine HCl formulations was demonstrated as the 90% confidence intervals of the geometric least squares mean ratio for Cmax, AUClast, and AUC of fexofenadine were all within the bioequivalence range of 0.80‐1.25. There were no serious adverse events (AEs) or study discontinuations due to treatment‐emergent AEs with either fexofenadine HCl formulation. The new paraben‐free fexofenadine HCl 30‐mg oral suspension and marketed fexofenadine HCl 30‐mg pediatric oral suspension are bioequivalent under fasting conditions, with no safety concerns and a safety profile consistent with the known profile of fexofenadine.

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“…Generally, healthy adult volunteers are used for a BE study, and blood is frequently sampled to assess pharmacokinetic (PK) equivalence using noncompartmental analysis (NCA) 22 . However, a situation in which a pediatric subject is required for a BE assessment may arise; the absorption profile of the formulation may differ between adults and pediatrics 23,24 . Because the frequency and sample volume of blood collection are more limited in pediatrics than in adults, the blood sampling schedule must be refined.…”

Section: Introductionmentioning

confidence: 99%

“… 22 However, a situation in which a pediatric subject is required for a BE assessment may arise; the absorption profile of the formulation may differ between adults and pediatrics. 23 , 24 Because the frequency and sample volume of blood collection are more limited in pediatrics than in adults, the blood sampling schedule must be refined. Current schedule optimization methods are unable to reduce the sampling to a satisfactory level.…”

Section: Introductionmentioning

confidence: 99%

Computational design of clinical trials using a combination of simulation and the genetic algorithm

Tsuchiwata

Tsuji

2023

CPT Pharmacom & Syst Pharma

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Artificial intelligence (AI) has come to be used in various technological fields in recent years. However, there have been no reports of AI-designed clinical trials. In this study, we tried to develop study designs by a genetic algorithm (GA), which is an AI solution for combination optimization problems. Specifically, the computational design approach was applied to optimize the blood sampling schedule for a bioequivalence (BE) study in pediatrics and optimize the allocation of dose groups for a dose-finding study. The GA could reduce the number of blood collection points from 15 (typical standard) to seven points without meaningful impact on the accuracy and precision of the pharmacokinetic estimation for the pediatric BE study. For the dose-finding study, up to 10% reduction of the total number of required subjects from the standard design could be achieved. The GA also created a design that would lead to a drastic reduction of the required number of subjects in the placebo arm while keeping the total number of subjects at a minimum level. These results indicated the potential usefulness of the computational clinical study design approach for innovative drug development. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?The quality of a clinical study design is a key component of the success of the clinical development of new medicine. WHAT QUESTION DID THIS STUDY ADDRESS?This study assessed the possibility of creating a novel and innovative clinical study design using artificial intelligence (AI)-based approaches like genetic algorithm, to overcome the limitations of traditional standard and empirical choices. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?The results of this study suggest that an AI-based approach could help the development of a clinical study design. HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS?The findings suggest that computer recommendations of a study design may result in opportunities to input novel and innovative ideas into model-informed drug development.

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Development of a Pediatric Relative Bioavailability/Bioequivalence Database and Identification of Putative Risk Factors Associated With Evaluation of Pediatric Oral Products

Cited by 6 publications

References 103 publications

Quantification of Fluid Volume and Distribution in the Paediatric Colon via Magnetic Resonance Imaging

Quantification of Fluid Volume and Distribution in the Paediatric Colon via Magnetic Resonance Imaging

Bioequivalence of 2 Pediatric Formulations of Fexofenadine Hydrochloride Oral Suspension

Computational design of clinical trials using a combination of simulation and the genetic algorithm

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